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Cerebrovascular pathologies occur in up to 80% of cases of Alzheimer's disease; however, the underlying mechanisms that lead to perivascular pathology and accompanying blood–brain barrier (BBB) disruption are still not fully understood. We have identified previously unreported mutations in colony stimulating factor‐1 receptor ( CSF‐1R ) in an ultra‐rare autosomal dominant condition termed adult‐onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP). Cerebrovascular pathologies such as cerebral amyloid angiopathy (CAA) and perivascular p‐Tau were some of the primary neuropathological features of this condition. We have identified two families with different dominant acting alleles with variants located in the kinase region of the CSF‐1R gene, which confer a lack of kinase activity and signalling. The protein product of this gene acts as the receptor for 2 cognate ligands, namely colony stimulating factor‐1 (CSF‐1) and interleukin‐34 (IL‐34). Here, we show that depletion in CSF‐1R signalling induces BBB disruption and decreases the phagocytic capacity of peripheral macrophages but not microglia. CSF‐1R signalling appears to be critical for macrophage and microglial activation, and macrophage localisation to amyloid appears reduced following the induction of Csf‐1r heterozygosity in macrophages. Finally, we show that endothelial/microglial crosstalk and concomitant attenuation of CSF‐1R signalling causes re‐modelling of BBB‐associated tight junctions and suggest that regulating BBB integrity and systemic macrophage recruitment to the brain may be therapeutically relevant in ALSP and other Alzheimer’s‐like dementias. Synopsis Two familial cohorts of ALSP, with novel pathological CSF1R variants were examined and an associating cerebrovascular amyloid‐β pathology identified. Deficits in peripheral macrophage function and blood‐brain barrier maintenance identified and suggested to contribute to ALSP. Two novel pathological CSF1R mutations were identified and characterised, indicating the observed pathology to be driven by CSF1R haploinsufficiency. Cerebral amyloid angiopathy (CAA) was identified as a novel accompanying pathology in ALSP, providing a potential single‐gene mutation capable of driving CAA itself. CSF1R heterozygosity was shown to negatively impact macrophage differentiation, phagocytosis and chemotaxis to the brain in response to amyloid‐β. Microglia heterozygous for Csf1r were shown to be uniquely capable of downregulating tight junction expression in brain endothelial cells. Graphical Abstract Two familial cohorts of ALSP, with novel pathological CSF1R variants were examined and an associating cerebrovascular amyloid‐β pathology identified. Deficits in peripheral macrophage function and blood‐brain barrier maintenance identified and suggested to contribute to ALSP.

Microglia, the brain immune cells, support neurons by producing several established neurotrophic molecules including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Modern analytical techniques have identified numerous phenotypic states of microglia, each associated with the secretion of a diverse set of substances, which likely include not only canonical neurotrophic factors but also other less-studied molecules that can interact with neurons and provide trophic support. In this review, we consider the following eight such candidate cytokines: oncostatin M (OSM), leukemia inhibitory factor (LIF), activin A, colony-stimulating factor (CSF)-1, interleukin (IL)-34, growth/differentiation factor (GDF)-15, fibroblast growth factor (FGF)-2, and insulin-like growth factor (IGF)-2. The available literature provides sufficient evidence demonstrating murine cells produce these cytokines and that they exhibit neurotrophic activity in at least one neuronal model. Several distinct types of neurotrophic activity are identified that only partially overlap among the cytokines considered, reflecting either their distinct intrinsic properties or lack of comprehensive studies covering the full spectrum of neurotrophic effects. The scarcity of human-specific studies is another significant knowledge gap revealed by this review. Further studies on these potential microglia-derived neurotrophic factors are warranted since they may be used as targeted treatments for diverse neurological disorders.

MMP‐21 is a newly identified member of the matrix metalloproteinase family and has been reported to regulate both embryonic development and tumor progression. However, the roles of MMP‐21 in hemofiltrate C–C chemokine (HCC) remain largely unclear. In this study, we used western blot, qPCR and immunohistochemistry (IHC) to determine the upregulation of MMP‐21 in HCC tissues, and showed that the increase in MMP‐21 was associated with vascular invasion and poor prognosis. Although changing levels of MMP‐21 in HCC cell lines had no significant effect on cell migration or invasion abilities in in vitro transwell tests, both IHC analysis and in vivo mouse models proved that upregulated MMP‐21 promoted metastasis. Functional enrichments of MMP‐21 using The Cancer Genome Atlas (TCGA) data suggested that MMP‐21 might regulate metastasis via macrophages. Further experiments proved that MMP‐21 enhanced macrophage recruitment by increasing CCL‐14 levels and promoted M2‐type polarization of macrophage by elevating the expression of CSF‐1 and FGF‐1. Taken together, this study revealed that MMP‐21 controlled the tumor microenvironment remodeling and functional regulation of macrophages to regulate HCC metastasis. MMP‐21 enhanced macrophage recruitment by upregulating CCL‐14 levels and promoted macrophage M2‐type polarization by increasing the expression of CSF‐1 and FGF‐1, and ultimately facilitated metastasis in HCC.

Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following hematopoietic cell transplantation (HCT), patients are susceptible to Herpesviridae including cytomegalovirus (CMV). We show in a murine model of HCT that macrophage colony‐stimulating factor (M‐CSF) promoted rapid antiviral activity and protection from viremia caused by murine CMV. M‐CSF given at transplantation stimulated sequential myeloid and natural killer (NK) cell differentiation culminating in increased NK cell numbers, production of granzyme B and interferon‐γ. This depended upon M‐CSF‐induced myelopoiesis leading to IL15Rα‐mediated presentation of IL‐15 on monocytes, augmented by type I interferons from plasmacytoid dendritic cells. Demonstrating relevance to human HCT, M‐CSF induced myelomonocytic IL15Rα expression and numbers of functional NK cells in G‐CSF‐mobilized hematopoietic stem and progenitor cells. Together, M‐CSF‐induced myelopoiesis triggered an integrated differentiation of myeloid and NK cells to protect HCT recipients from CMV. Thus, our results identify a rationale for the therapeutic use of M‐CSF to rapidly reconstitute antiviral activity in immunocompromised individuals, which may provide a general paradigm to boost innate antiviral immunocompetence using host‐directed therapies. Synopsis Herpesviridae like CMV are a major cause of morbidity and mortality in patients after HCT. Therapies reconstituting the host's antiviral immunocompetence for prophylaxis and treatment are an unmet medical need since licensed therapies are either insufficiently effective or have severe side effects. M‐CSF protects from lethal murine CMV viremia during leukopenia following hematopoietic cell transplantation, a vulnerable period of immunosuppression, by rapidly reconstituting donor hematopoietic stem and progenitor cells. M‐CSF stimulates a coordinated myeloid and NK cell differentiation program resulting in increased NK cell numbers and activity, which depends on M‐CSF‐induced myelopoiesis generating IL‐15‐producing monocytes and I‐IFN‐producing pDCs. No impairment of long‐term hematopoietic stem cell engraftment or acute graft‐versus‐host‐disease after M‐CSF treatment was observed. In G‐CSF‐mobilized human PBMCs M‐CSF also stimulates monopoiesis, IL15Rα expression in monocytes and functional NK cell differentiation. M‐CSF could provide a general host‐directed antiviral cytokine therapy, to complement pathogen‐directed antiviral therapies in immunosuppressed conditions beyond HCT, such as post‐chemotherapy leukopenia or septicemia. Graphical Abstract Herpesviridae like CMV are a major cause of morbidity and mortality in patients after HCT. Therapies reconstituting the host's antiviral immunocompetence for prophylaxis and treatment are an unmet medical need since licensed therapies are either insufficiently effective or have severe side effects.

The role of miRNAs (microRNAs) has been implicated in glioma initiation and progression, although the inherent biochemical mechanisms still remain to be unravelled. This study strived to evaluate the association between CSF‐1 and miR‐1254 and their effect on advancement of glioma cells. The levels of miR‐1254 in glioma cells and tissues were determined by real‐time RT‐PCR. Proliferation, apoptosis and cell cycle arrest, invasion and migration, were assessed by CCK‐8 assay, colony formation assay, flow cytometry, transwell assay and wound‐healing assay, respectively. The targeted relationship between miR‐1254 and CSF‐1 was confirmed by dual‐luciferase reporter assay. The effects of CSF‐1 on cellular functions were also assessed. The in vivo effect of miR‐1254 on the formation of a tumour was explored by using the mouse xenograft model. We found in both glioma tissues and glioma cells, the down‐regulated expressions of miR‐1254 while that of CSF‐1 was abnormally higher than normal level. The target relationship between CSF‐1 and miR‐1254 was validated by dual‐luciferase reporter assay. The CSF‐1 down‐regulation or miR‐1254 overexpression impeded the invasion, proliferation and migratory ability of U251 and U87 glioma cells, concurrently occluded the cell cycle and induced cell apoptosis. Moreover, in vivo tumour development was repressed due to miR‐1254 overexpression. Thus, CSF‐1 is targeted directly by miR‐1254, and the miR‐1254/CSF‐1 axis may be a potential diagnostic target for malignant glioma.

Aim Aging‐related cognitive decline is closely linked to the reduced function of neural progenitor/stem cells (NPSCs), which can be influenced by the neural microenvironment, particularly astrocytes. The aim of this study was to explore how astrocytes affect NPSCs and cognitive function during aging. Methods H2O2‐treated astrocytes were used to mimic the aging phenotype of astrocytes. Proteomic analysis identified altered protein expression, revealing high levels of colony‐stimulating factor‐1 (CSF‐1) in the supernatant of H2O2‐treated astrocytes. Primary NPSCs were isolated and cultured in vitro, then stimulated with varying concentrations of recombinant CSF‐1 protein to assess its effects on NPSC proliferation, differentiation, and apoptosis. Transcriptome sequencing identified miR‐484 related to CSF‐1 in H2O2‐treated astrocytes, and a dual‐luciferase assay verified the interaction between miR‐484 and CSF‐1. The impact of miR‐484 overexpression on NPSC function and cognitive restoration was evaluated both in vitro and in vivo (in 20‐month‐old rats). Results High concentration of CSF‐1 inhibited the NPSC proliferation and differentiation into neurons while inducing apoptosis. Overexpression of miR‐484 downregulated CSF‐1 expression by binding to its 3' untranslated region, thereby promoting the NPSC proliferation and differentiation into neurons. In 20‐month‐old rats, miR‐484 overexpression improved spatial learning and memory in the Morris water maze, increased NPSC proliferation, and reduced apoptosis. Conclusion Our findings reveal that miR‐484 regulates CSF‐1 to influence NPSC proliferation, differentiation into neurons, and apoptosis, consequently improving cognitive function in 20‐month‐old rats. This study provides a foundation for developing therapeutic strategies targeting age‐related hippocampal cognitive impairments. miR‐484 was shown to negatively regulate CSF‐1 expression and promote NPSC neurogenesis, decreasing NPSC apoptosis.

We present a case of a 40-year-old man with rapid decline in cognition followed by Parkinsonism, apraxia and stimulus sensitive myoclonus within 9 months of onset. Magnetic Resonance imaging (MRI) showed periventricular confluent white matter changes with persistent diffusion restriction even after 9 months. Clinical exome sequencing showed colony stimulating factor 1 receptor (CSF1R) gene mutation. The phenotype, MRI and genotype are suggestive of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). This is the first case being reported from India. Differential diagnosis of young onset dementia is broad. Therefore, finding the exact etiology is challenging. Neuroimaging and genetic analysis greatly aid in the final diagnosis.

Objective To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of iluzanebart, a fully human monoclonal antibody TREM2 (triggering receptor expressed on myeloid cells 2) agonist, after single‐ (SAD) and multiple‐ascending‐dose (MAD) administration. Methods Healthy adult volunteers (N = 136) received intravenous placebo or iluzanebart 1–60 mg/kg (SAD) or 10–60 mg/kg (MAD) followed by serial pharmacokinetics and safety assessments. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory evaluations. Pharmacokinetics were assessed through noncompartmental analysis. The study also included open‐label cohorts (3, 10, 20, 40, 60 mg/kg SAD; 10, 20, 40 mg/kg MAD) for cerebrospinal fluid (CSF) collection for exploratory pharmacodynamic biomarker analysis. Results Iluzanebart was safe and well tolerated following single and multiple doses of up to 60 mg/kg. Most AEs were mild and resolved spontaneously. The most frequently reported AE was pruritus. No serious AEs or investigational product–related clinically meaningful changes in vital signs, electrocardiograms, or laboratory assessments were reported. Iluzanebart serum exposure was related to dose, with a 29‐day half‐life that is supportive of monthly dosing and confirmed central nervous system (CNS) exposure (≈0.15% CSF‐to‐serum ratio). Durable and dose‐dependent target engagement, evidenced by marked reductions in soluble TREM2 and increased soluble CSF1R (colony‐stimulating factor 1 receptor) and osteopontin/SPP1 (secreted phosphoprotein 1) levels in CSF, was observed, indicating that iluzanebart changes microglial activity following single and repeat dosing. Interpretation Iluzanebart demonstrated favorable safety, tolerability, pharmacokinetics, and pharmacological activity in the CNS, supporting further clinical development for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia.

Intestinal inflammation associated with inflammatory bowel disease (IBD) is typically characterized by an inflammatory cell infiltrate and pro-inflammatory cytokine production. Of particular interest, the frequency of colony stimulating factor-1 (CSF-1)-expressing cells is increased in active lesions. In this study, we have investigated the role of CSF-1 in mucosal inflammation, using a murine model of colitis induced by dextran sulfate sodium (DSS).MethodsA neutralizing anti-CSF-1 antibody was administered to Balb/c mice that received DSS in their drinking water. Signs of colitis, such as clinical disease score, cellular infiltrate, and cytokine production, were assessed.ResultsAdministration of a neutralizing anti-CSF-1 antibody significantly inhibited DSS-induced colitis. Clinical symptoms, such as weight loss and the appearance of diarrhea or fecal blood, were reduced by CSF-1 blockade; histologic scores were also improved. The cellular infiltrate of macrophages and T cells was inhibited and a trend toward reduced production of pro-inflammatory cytokines was noted.ConclusionsThis is the first study to demonstrate that CSF-1 plays an important role in mediating intestinal mucosal inflammation and therefore may prove to be an attractive therapeutic target for intestinal diseases such as inflammatory bowel disease.

There are very few studies describing the preventive effect of macrophage colony‐stimulating factor (M‐CSF/CSF‐1) on chemotherapy‐induced infection. In this study, we evaluated the changes in superoxide anion production by granulocytes before and after chemotherapy in ovarian cancer patients and investigated the preventive effect of M‐CSF on chemotherapy‐induced febrile neutropenia. Three courses of chemotherapy [paclitaxel 180 mg/m2 and carboplatin (area under the curve; AUC 5)] were administered to 32 ovarian cancer patients, and seven patients presented febrile neutropenia. In the 25 afebrile patients, the percentage of superoxide anion production by granulocytes was significantly decreased from 86.5±7.7 (%) to 75.1±8.8 (%) at day 7 and 71.0±6.3 (%) at day 14 without administration of CSF. However, in the patients who presented febrile neutropenia, it was more severely decreased from 86.8±6.8 (%) to 60.0±9.9 (%) at day 7 and 56.8±5.0 (%) at day 14 without administration of CSF. When M‐CSF was administered to all patients in the next course with the same dose of chemotherapy, the incidence of febrile neutropenia was significantly decreased (P=0.0195), and the duration of fever (≫38.0°C) and high serum C‐reactive protein (CRP) (≫2.0 mg/dl) were also significantly shortened (P=0.0023, P=0.0051). Moreover, in these M‐CSF‐treated patients, the percentage of superoxide anion production by granulocytes was maintained at the level before chemotherapy. These findings indicate that severe impairment of granulocyte function leads to febrile neutropenia, and that M‐CSF reduces the incidence of febrile neutropenia by maintaining or improving granulocyte function.